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J. Biol. Chem., Vol. 283, Issue 20, 14144-14152, May 16, 2008

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Regulation of Telomeric Repeat Binding Factor 1 Binding to Telomeres by Casein Kinase 2-mediated Phosphorylation^*

Mi Kyung Kim, Mi Ran Kang, Hyung Wook Nam^¶, Young-Seuk Bae^||, Yu Sam Kim^¶, and In Kwon Chung¹

From the Department of Biology and Molecular Aging Research Center, ^¶Department of Biochemistry, and Protein Network Research Center, Yonsei University, Seoul 120-749 and the ^||Department of Biochemistry, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea

Telomere maintenance is essential for continued cell proliferation and chromosome stability. Telomeres are maintained by telomerase and a collection of associated proteins. The telomeric protein telomeric repeat binding factor 1 (TRF1) negatively regulates telomere length by inhibiting access of telomerase at telomere termini. Here we report that TRF1 interacts with the β subunit of casein kinase 2 (CK2) and serves as a substrate for CK2. CK2-mediated phosphorylation is required for the efficient telomere binding of TRF1 in vitro and in vivo. Inhibition of CK2 by the CK2 inhibitor 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole decreased the ability of TRF1 to bind telomeric DNA. The resulting telomere-unbound form of TRF1 was then ubiquitinated and degraded by the proteasome. Partial knockdown of CK2 by small interfering RNA resulted in removal of TRF1 from telomeres and subsequent degradation of TRF1. Mapping of the CK2 target site identified threonine 122 as a substrate in TRF1. A threonine to alanine change at this position led to a diminished DNA binding due to reduced dimerization of TRF1. In addition, phosphorylation of threonine 122 seemed critical for TRF1-mediated telomere length control. Our findings suggest that CK2-mediated phosphorylation of TRF1 plays an important role in modulating telomere length homeostasis by determining the levels of TRF1 at telomeres.

Received for publication, December 10, 2007 , and in revised form, March 13, 2008.

^* This work was supported in part by grants from the Korean Ministry of Health and Welfare through the Molecular Aging Research Center, from the Korea Science and Engineering Foundation through the Protein Network Research Center, and from Seoul Development Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biology, Yonsei University, 134 Shinchon-dong, Seoul 120-749, Korea. Tel.: 82-2-2123-2660; Fax: 82-2-364-8660; E-mail: topoviro{at}yonsei.ac.kr.

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